Epinephrine, also known as 4-[(1 R)-1-Hydroxy-2-(methylamino)ethyl]-1,2-benzenediol, is the active principle of the adrenal medulla and an endogenous catecholamine which acts directly on both alpha and beta adrenergic receptors. When used in pharmaceutical compositions, epinephrine can act as a non-selective alpha and beta adrenergic agonist and can work rapidly to improve breathing, stimulate the heart, raise dropping blood pressure, reverse hives, and reduce swelling of the face, lips, and throat. Uses for epinephrine include emergency treatment of allergic reactions (Type 1), including anaphylaxis, induction and maintenance of mydriasis during intraocular surgery, treatment of bronchospasm, sensitivity reactions, cardiac arrhythmias, GI and renal hemorrhage, superficial bleeding, premature labor, hypoglycemia, and cardiogenic, hemorrhagic, and traumatic shock. Epinephrine can also be used to increase blood flow in ACLS during CPR, as an adjunct to local anesthesia, and for radiographic uses.
Epinephrine is soluble in water at acidic pH, yet at neutral or basic pH is insoluble in water. Further, epinephrine at mildly-acidic pH is notoriously vulnerable to oxidative degradation to epinephrine sulfonate, an undesirable contaminant. Given these two constraints, the art thus teaches to formulate epinephrine as an acidic solution at a pH as low as 2. Such solutions are then administered by injection, as a nasal spray etc.
LOBRUTTO, Rosario et al., Pre-Filled Syringe, PCT WO/2018/130963, teaches a pre-filled syringe, an auto-injector device comprising such pre-filled syringe, a method of administering a pharmaceutical composition with such auto-injector device, and a manufacturing method for such auto-injector device. The pre-filled syringe comprises a container and a needle. The container is filled with a solution of epinephrine, a buffer, and water. The disclosure teaches, “The buffer is configured to buffer in a pH range between 3 and 4.” See Abstract. This acidic pH assures that the epinephrine active is dissolved into solution and remains stable.
SURAKITBANHARN, Yosyong et al., Stabilization Of Epinephrine Formulations, PCT WO/12017/218918, teaches epinephrine formulations in aqueous solution for medicinal products that enhance the physicochemical stabilities of epinephrine and extend the product shelf life. In some instances, the formulations comprise epinephrine or a salt thereof, a complexing agent, and a “non-sulfite” antioxidant. The epinephrine formulations substantially demonstrated the superior physicochemical stabilities to conventional sulfite formulation of commercial medications currently available. In some instances, sulfite-free formulations further provide further benefit (e.g., safety benefits) to sulfite-sensitive patients. The compositions, methods for preparing the formulations, and methods of using the same (e.g., in the treatment of anaphylaxis) are also provided. The disclosure teaches to use hydrochloric acid to adjust pH to 2.2-5.0. See e.g., [0012], [0015], [0029].
BAILLIE, Alan, J. et al., Stabilised Composition Comprising At Least One Adrenergic Compound, PCT WO/2010/139752, teaches a stabilized composition comprising at least one adrenergic compound and at least one antioxidant selected from the group consisting of a bisulfite, a metabisulfite and a sulfite compound. See e.g., page 2 line 25; page 5 line 2.
KANNAN, Vinayagam et al., Epinephrine Formulations, PCT WO/2016/149028, teaches pharmaceutical compositions comprising epinephrine, methods of administration, and methods of making the same. The patent claims a composition comprising epinephrine and/or salts thereof, a tonicity regulating agent, an antioxidant, a transition metal complexing agent, and a buffer system consisting of a strong acid (i.e., HCl) as a “pH lowering agent” and a combination of tartaric acid and NaOH as a “pH raising agent”. To assure that the system maintains an acidic pH, the disclosure teaches the pH raising agent should have a pKa value within the range of about 2 to 5, preferably within the range of about 3 to 4.5, more preferably within the range of about 3.5 to 4.5, and most preferably about 4. Similarly, the disclosure teaches to use a pH raising agent with have a buffer range from a pH of about 2 to 5, preferably from a pH of about 3 to 4.5, and most preferably from a pH of about 3.5 to 4.5. See [0031] to [0032]. This acidic pH assures that the epinephrine active is dissolved into solution.
LEBEDYEVA, Iryna, O. et al., Compounds, Compositions, And Methods Of Making And Using The Same, PCT WO/2017/066787, teaches epinephrine solutions “wherein the pH of the compound of Formula (I) or hydrate thereof ranges from about 3.5 to about 5.5.” See e.g., claim 62.
The art thus teaches to formulate epinephrine as an acidic solution at a pH as low as 2, which solutions may be administered by injection, or as a nasal spray etc. Such acidic solutions, however, may be irritating. Further, administering a liquid concomitantly requires the use of e.g., a metered-dose inhaler or a metered-dose injector. Such devices add significantly to the expense of the product. Such devices also greatly increase the number of potential failure modes, a risk which Failure Mode, Effects And Criticality Analysis (FMECA) attempts to reduce. Further, in certain usage environments liquid solution formulations may be unsuitable or unstable.
There is currently a need in the art for improved epinephrine-containing pharmaceuticals. It is an object of the present invention to provide an epinephrine-containing pharmaceutical composition that addresses some of the limitations of present formulations.